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An immunoassay method based on the labelling of an antigen with a transition-metal carbonyl organometallic marker and detection of the label by Fourier transform infrared (FT-IR) spectroscopy is described. The viability of this novel non-isotopic approach, termed infrared immunoassay (IRIA), has been evaluated in the quantitative determination of the tricyclic antidepressant nortriptyline.
This study concentrates on the production of covalent molecular imprint polymers (MIPs) as highly selective sorbents for nortriptyline (NOR), a representative tricyclic antidepressant (TCA). The functionalized template contains a polymerizable 4-vinylphenyl carbamate moiety used to bind the template molecule to the polymer matrix. Polymerization with a cross-linker followed by hydrolytic cleavage of the labile carbamate functionality leaves an MIP with selective binding sites capable of binding template through hydrogen bonding interactions. Demonstrated chromatographically through a "selection index", these MIPs showed high selectivity for the template molecule (NOR) among a library of structurally similar compounds. The recognition was found to correlate with structural similarity to the template compound. A direct comparison between covalent and non-covalent molecular imprinting strategies reveals a great deal of improvement in the peak shape of the retained compound resulting from covalent imprinting (evidenced by peak asymmetry factors A.).
Gas chromatography was used to determine plasma levels of amitriptyline, nortriptyline and their 10-hydroxy derivatives after conversion to the dehydro compounds by heating with acid. The primary amine 10-hydroxydesmethylnortriptyline is also dehydrated and the dehydro compound coincides on the chromatogram with dehydronortriptyline. Treatment of the extract with salicylaldehyde selectively removed the primary amine, which was determined by difference. Cis- and trans-hydroxydesmethylnortriptyline were isolated from urine by thin-layer chromatography and used to standardize the estimation. The stability of all the metabolites in plasma was investigated. Results are given for hydroxydesmethylnortriptyline levels in the plasma of 41 patients treated with amitriptyline.
Internal-surface reversed-phase (ISRP) silica supports having N-octanoylaminopropyl phases bound to the internal surfaces of the porous silica and N-(2,3-dihydroxypropyl)aminopropyl phases bound to the external surfaces were synthesized from silica particles differing in nominal pore diameters and specific surface areas. These ISRP supports were characterized with regard to physical and chromatographic properties. The support with an N-octanoylaminopropyl phase coverage of 485 mumol/g and an average pore diameter of 65 A was the most suitable for the direct-injection determination of hydrophilic or hydrophobic drugs in serum or plasma. Non-steroidal anti-inflammatory (acetylsalicylic acid and salicylic acid) and tricyclic antidepressant drugs (desipramine and nortriptyline) in serum were successfully determined with this support and an acidic eluent.
A gas chromatographic method for the determination of perphenazine (Tri-lafon) and its main metabolite in human plasma, perphenazine sulphoxide, has been developed. The procedure involves the use of an electron capture detector and permits the determination of the drug and its metabolite at concentrations down to 0.2 mug/l. This is sufficient for analyzing plasma from patients on ordinary treatment with perphenazine. Tests for specificity revealed no interference by nortriptyline or biperidine.
High-performance thin-layer chromatography affords a rapid, sensitive method for determination of psychopharmacologic agents in blood serum samples. Quantitation of the representative drugs chlorpromazine, amitriptyline, nortriptyline, imipramine, and desipramine at levels as low as 5 ng/ml is demonstrated by scanning the developed thin-layer plates with a chromatographic spectrophotometer in the ultraviolet absorption mode. Neither derivatization prior to, nor color development after chromatographic separation is required to achieve sensitivity and reproducibility of determinations.
The drug-drug interactions with fluoxetine, a pure serotonergic reuptake blocker with a unique profile of side effects, have not been studied adequately. This preliminary report shows that desipramine and nortriptyline plasma levels are markedly increased at steady state (2 to 11 times) when coadministered with fluoxetine. This appears to be the result of the inhibition of the P450 enzyme system of the liver by fluoxetine, resulting in increased plasma levels of drugs metabolized by this system. Research must promptly address drug-drug interactions with fluoxetine since potentially all psychotropic drugs (except for lithium) and many medically indicated drugs could also have significant drug-drug interactions with fluoxetine.
Depression and anxiety disorders are common clinical problems in organ transplant recipients, but there is a paucity of clinical data to inform the selection of psychopharmacologic treatment. The authors retrospectively compared 13 depressed organ transplant recipients treated with fluoxetine with 13 nondepressed matched control recipients and 11 transplant recipients treated with tricyclic antidepressants (nortriptyline or desipramine). Blood level:dose ratios and dose-response relationships for cyclosporine were virtually identical in all three groups before and during treatment. No increase in adverse clinical events was detected in either active treatment group compared with the control subjects. Fluoxetine appeared to be well tolerated by this population of transplant patients, and the authors failed to detect significant alterations in cyclosporine levels or graft function.
54 patients in five centres participated in a study of the relationship between steady-state plasma-levels of amitriptyline (AT) and its active metabolite nortriptyline (NT) and therapeutic response. The participants were inpatients who, after a 7-12 day period of assessment, were rated greater than or equal to 16 on the Hamilton rating scale for depression. They were given 75 mg of amitriptyline for 3 days and then 150 mg daily for an active-treatment period of 6 weeks. Clinical ratings and plasma-samples were obtained at baseline then at 2, 4, and 6 weeks after starting therapy. Contrary to the findings of three previous trials, no important correlations were found between steady-state plasma-levels and therapeutic outcome or corrected side-effects. Corrected side-effects correlated negatively with therapeutic outcome. There seems little advantage in routine monitoring of AT and NT, since variations in plasma-levels do not account for the considerable variation in therapeutic outcome.
This article describes a post-hoc analysis of clinical and psychosocial factors and beliefs about health associated with treatment outcome in a sample of depressed primary care patients (N=181) randomly assigned to a standardized treatment or physician's usual care (UC). Different factors were found to predict clinical outcomes for treatment modality [UC vs. interpersonal psychotherapy (IPT) or nortriptyline (NT)] and the type of outcome evaluated (i.e., depressive symptoms at 8 months or symptomatic and functional recovery at 8 months). Factors associated with treatment-specific outcomes are also described. Consistent with prior studies, lower depressive symptom severity at 8 months was associated with higher baseline functioning, minimal medical co-morbidity, race, and standardized pharmacologic or psychotherapeutic treatment. Additionally, an interaction between treatment modality and health locus of control indicated that individuals perceiving more self-control of their health and who received a standardized treatment experienced greater depressive symptom reduction at 8 months. Factors associated with symptomatic and functional recovery from the depressive episode were also examined. Patients who received a standardized treatment (IPT or NT) perceived greater control of their health and lacked a lifetime generalized anxiety disorder or panic disorder were more likely to recover by month 8 than those who received usual care. While clinical severity and treatment adequacy play an important role in both symptomatic improvement and full recovery from a depressive episode, other key factors such as health beliefs and non-depressive psychopathology also influence recovery.
BACKGROUND: Although active maintenance treatments appear superior to placebo in preventing depression recurrence in older adults, few data are available to guide maintenance modality selection to maximize the probability of continued wellness for a given patient. Patients' temporal patterns of acute treatment response may predict who requires which maintenance therapy to remain well. METHODS: Depression levels were observed over 16 weeks of combined nortriptyline (NT) and interpersonal psychotherapy (IPT) in 140 persons aged >or=60 years with recurrent major depression. Subjects were empirically classified into four groups: rapid, sustained responders; delayed, sustained responders; mixed responders without sustained improvement; prolonged nonresponders. Groups were compared on subsequent recovery rates and on time to depression recurrence after randomization to 3 years of combined maintenance therapy (monthly IPT with NT), monotherapy (either IPT or NT alone), or medication clinic with placebo. Pretreatment psychosocial and clinical variables were controlled. RESULTS: Initial response profile predicted ultimate recovery rates, as well as who remained well, given the maintenance treatment received. Rapid initial responders showed lower recurrence risk with either combined or monotherapy, relative to placebo. Specific types of monotherapy appeared equally effective in rapid responders. In initially mixed responders, only combined therapy was superior to placebo. It was marginally superior to monotherapy. For delayed responders, combined therapy was superior to placebo; monotherapy did not differ from the other maintenance conditions. Prolonged nonresponders did not benefit from maintenance treatment. LIMITATIONS: Subjects had only recurrent, unipolar depression. Initial response profile groups were established empirically and require replication. Sample sizes in initial response profile by maintenance treatment cells were small. CONCLUSION: The ability to match patients to maintenance treatments more likely to prevent recurrence may be enhanced by considering the temporal profile of initial response to acute treatment.
BACKGROUND: The literature on acoustic measures of voice in depression is reviewed. Authors have separated results derived from studies of automatic speech, such as counting or reading, from free speech. Free speech requires cognitive activity such as word finding and discourse planning in addition to the motor activity of automatic speech. Also, results have been less ambiguous if homogeneous groups of agitated or retarded depressed patients were examined. METHODS: These distinctions are applied to the results of a 12-week double-blind treatment trial that compared response to nortriptyline (25-100 mg/day) with sertraline (50-150 mg/day). Twelve male and ten female elderly depressed patients and an age-matched normal control group (n=19) were studied. Patients were divided into retarded or agitated groups on the basis of ratings. Results from measures of fluency (speech productivity and pausing) and prosody (emphasis and inflection) are described. RESULTS: Depressed patients showed less prosody than the normal subjects. Improvement in the retarded group was reflected in briefer pauses but not longer utterances. There was a trend in the agitated group for improvement to be reflected in the utterance but not the pause measure. CONCLUSIONS: Clinical impressions are substantially related to acoustic parameters. Temporal changes associated with depression appear to reflect the depressed state whereas prosodic features seem to reflect a depressed trait. Acoustic measures of the patient's speech may provide objective procedures to aid in the evaluation of depression. Limitations of the study are discussed.
OBJECTIVE: The authors examined elderly patients with major depression to determine the relationship of current age to treatment response course and success rate. METHODS: Three studies of elderly depressed patients provided data on antidepressant treatment response in 323 subjects, treated in protocols using either nortriptyline or paroxetine. We grouped the subjects by current age: 'young-old' (59-69, N=163), 'middle-old' (70-75, N=80), and 'older-old' (76-99, N=80). We employed mixed-effect random regression analyses to examine Hamilton Rating Scale for Depression scores over 12 weeks of acute treatment. RESULTS: Older-old patients responded as quickly and successfully as the young- and middle-old. CONCLUSIONS: Major depression in the very old can be treated as successfully as in early old age.
BACKGROUND: Studies attempting to identify predictors of antidepressant response in patients with major depression have reported inconsistent results. One explanation may be the different definitions of outcome used. METHODS: 187 depressed subjects were recruited and were randomised to treatment with fluoxetine and nortriptyline. At baseline and 6 weeks, subjects completed Hamilton Depression Rating Scale HDRS-17 and 27, Montgomery Asberg Depression Rating Scale (MADRS), the Hopkins Symptom Checklist (SCL-90) and the Social Adjustment Scale (SAS) as well as the Clinical Global Impression Scale (CGI). Relationships among outcome measures were assessed. Receiver Operator Characteristic (ROC curves) were used to show the diagnostic ability of the MADRS and HDRS in predicting the clinician's rating. RESULTS: All outcome measures were moderately to highly correlated. All measures were significantly related to the clinician's global impression, but the strongest associations were with the MADRS score. Using ROC curves we showed that a score of 8 on the HDRS or 14 on the MADRS was the optimal compromise between sensitivity and specificity in dividing this sample into responders and non-responders. A 60% reduction in HDRS and MADRS scores rather than a 50% reduction appeared the most valid division between responders and non-responders. LIMITATIONS: We relied on clinician judgement as the validating criterion. The results only apply to a sample of moderately depressed outpatients. CONCLUSIONS: The MADRS score seemed to most accurately reflect a clinician's impression of change. Dividing a sample into responders and non-responders can be approached empirically.
BACKGROUND: Multiple lines of evidence suggest continuity from adolescent to adult depression, but treatment response is different in the two groups. There is some consensus that noradrenergic drugs are ineffective in adolescent depression. The aim of this study was to see whether this poor response extended to young adults. METHODS: Patients from two randomised studies on prediction of antidepressant response were used. The subjects were divided into a youth sample (ages 18-24) and an older sample (ages 25 and over). The 6-week percentage response, based on HDRS scores, and the number of patients in remission (i.e., HDRS < or =7) at 6 weeks were compared in subjects who received a serotonergic (clomipramine (mean dose 145 mg) and fluoxetine (mean dose 27 mg)) or a noradrenergic (desipramine (mean dose 200 mg) and nortriptyline (mean dose 100 mg)) antidepressant. RESULTS: There were no significant differences between the two studies, except for a small variation in baseline Hamilton scores. Young adults had a poorer response to noradrenergic antidepressants than they did to serotonergic antidepressants, whereas there was no differential response in the older age group. Young adults had a lower rate of remission on a noradrenergic antidepressant (38% noradrenergic versus 72% serotonergic) but there was no significant difference in remission rates in older adults (65% noradrenergic versus 57% serotonergic) or the sample as a whole (54% noradrenergic versus 62% serotonergic). LIMITATIONS: The age cut-off at 24 is somewhat arbitrary. One study was double-blind while the other was open. There was no placebo control. DISCUSSION: While the response rate to noradrenergic antidepressants in young adults is lower, it is not clear whether this is comparable to adolescents. The reasons for a reduced response may be related to maturation of the noradrenergic system in the brain. Our results suggest that age may be one factor to consider when choosing antidepressants for patients.
BACKGROUND: Late-life depression studies have found that comorbid anxiety, as a symptom or comorbid disorder, is associated with poorer treatment response and increased likelihood of dropout. This study evaluated the impact of comorbid anxiety on response, dropouts, and side effects, in elderly subjects treated for depression. METHODS: We analyzed data from a 12-week trial comparing nortriptyline and paroxetine in 116 patients aged 60 and older with depression. Subjects classified as having anxious depression were compared to those with nonanxious depression in terms of treatment response rate, time to response, dropout rate, and early side effects. The analysis was replicated with another study, in which 125 subjects aged 69 and older were treated openly with paroxetine and interpersonal psychotherapy. RESULTS: Anxious and nonanxious groups did not differ in terms of response rates, time to response, dropout rates, or time to dropout. Side effects declined more quickly and more significantly in the anxious group than in the nonanxious group. LIMITATIONS: Subjects were treated in a specialty mental health setting, and the findings may not apply in other settings. CONCLUSIONS: We found no association between comorbid anxiety and a poorer prognosis during acute treatment of late-life depression. For elderly patients with anxious depression, standardized treatment in the mental health sector is associated with a good response.
BACKGROUND: Some 10-15% of women experience postpartum-onset major depression (PPMD). The objective of this study was to determine if the Edinburgh Postnatal Depression Scale (EPDS) is an effective screen for major depression (MD) prospectively. The outcome of the study was identification of a recurrence of major depression in the first year postpartum by a clinical interview and the EPDS. We had the unique opportunity to examine the relationship between EPDS scores and PPMD. METHODS: Participants were pregnant women who had experienced an episode of previous PPMD but were well during their index pregnancy. This study was part of a double-blind, randomized clinical trial in which new mothers received nortriptyline or placebo within 24 h following delivery for prevention of PPMD. Recurrence of depression was established according to Research Diagnostic Criteria. Participants completed the EPDS weekly through 20 weeks postpartum and into a 1-year follow-up phase. RESULTS: Out of 50 women, 13 experienced recurrence of MD in the first 20 weeks postpartum with a total of 20 out of 50 recurring in the first year. The EPDS score of >9 at week 4 postpartum identified 60% of women who nurtured in the first 20 weeks and 80% who recurred in the first postpartum year. LIMITATIONS: The study population included only women who had a previous episode of postpartum depression. The generalizability to all women is limited. CONCLUSIONS: The EPDS is an effective depression screen for women who had a previous episode of PPMD. Clinical guidelines are provided for use of the EPDS to identify MD in the first postpartum year in primary care settings.
OBJECTIVE: To retrospectively determine whether race differentially influences treatment adherence and clinical outcomes among 68 African Americans and 92 whites treated for major depression in four urban, primary care settings. METHOD: Study participants were randomly assigned to standardized interpersonal psychotherapy or pharmacotherapy with nortriptyline, and were assessed at baseline, and successive time points up to 8 months for severity of depression, and mental and physical health-related functioning. RESULTS: Intent-to-treat analyses revealed no treatment or race-specific differences in symptomatic recovery when both groups were provided standardized psychotherapy or pharmacotherapy. However, African Americans had poorer functional outcomes than whites. CONCLUSIONS: African American and white primary medical care patients are effectively treated with standardized psychotherapy and pharmacotherapy. Future research should assess the impact of cultural context on symptom presentation, psychosocial functioning, and treatment adherence and response.